1. Field of the Invention
The invention relates to a process for preparing optically active 3-alkylcarboxylic acids. Optically active 3-alkylcarboxylic acids are important synthesis units for the preparation of active pharmaceutical ingredients. For example (R)-3-methylheptanoic acid and (R)-3-methylhexanoic acid find use as constituents and/or synthesis units of active ingredients for immune regulation.
2. Description of the Related Art
U.S. Pat. No. 5,245,079 discloses a process in which (R)-3-methylheptanoic acid and (R)-3-ethylheptanoic acid are prepared in a multistage synthesis sequence starting from racemic trans-4-hexen-3-ol and trans-4-hepten-3-ol. In this process, an optical resolution (Sharpless reaction) takes place in the first synthesis step. The yield of this step is firstly restricted to 50% of theory, and several reaction steps of the process secondly require reactions at temperatures of <−60° C., which makes the process uneconomical especially for use on an industrial scale.
JP 03095138 and WO 9322269 describe optical resolution processes for preparing (R)-3-methylheptanoic acid and (S)-3-methylheptanoic acid by crystallization with the aid of 1-phenylethylamine and 1-phenylpropylamine as chiral assistants. In the two processes, the optically active carboxylic acids are obtained in sufficient enantiomeric excess of >97% ee only after several successive crystallizations and recrystallizations. The low yields of up to <15% of theory and the high process complexity do not meet the requirements for an economically viable process on the industrial scale.
U. Berens, H.-D. Scharf, Synthesis, 1991, p. 832 discloses the preparation of (S)-4-benzyloxy-3-methyl-butanoic acid. In this preparation, (S)-1-benzyloxypropan-2-ol is activated by tosylation, di-tert-butyl malonate is alkylated with the tosylate in polar aprotic dimethylformamide with inversion, and the alkylated malonic ester is hydrolyzed and decarboxylated to give (S)-4-benzyloxy-3-methylbutanoic acid. The reaction of the open-chain secondary toluene-sulfonate of (S)-1-benzyloxypropan-2-ol with the potassium salt of di-tert-butyl malonate in dimethylformamide proceeds, however, with partial racemization and only 65% chemical yield. The overall yield over all stages is only 45%.
None of the processes known from the prior art affords optically active 3-alkylcarboxylic acids in simultaneously high chemical and optical yields under conditions which are realizable on the industrial scale and/or of economic interest.